WO2005108390A1 - Derives de l'indol-2-one traitant les troubles du snc, gastro-intestinaux, et cardio-vasculaires - Google Patents

Derives de l'indol-2-one traitant les troubles du snc, gastro-intestinaux, et cardio-vasculaires Download PDF

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Publication number
WO2005108390A1
WO2005108390A1 PCT/HU2005/000051 HU2005000051W WO2005108390A1 WO 2005108390 A1 WO2005108390 A1 WO 2005108390A1 HU 2005000051 W HU2005000051 W HU 2005000051W WO 2005108390 A1 WO2005108390 A1 WO 2005108390A1
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Prior art keywords
dihydro
indol
general formula
ethyl
halogen
Prior art date
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PCT/HU2005/000051
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English (en)
Inventor
Balázs VOLK
József Barkóczy
Gyula Simig
Tibor Mezei
Rita KAPILLERNÉ DEZSOFI
István Gacsályi
Katalin Pallagi
Gábor Gigler
György Lévay
Krisztina MÓRICZ
Csilla Leveleki
Nóra SZIRAY
Gábor SZÉNÁSI
András Egyed
László Gábor HÁRSING
Original Assignee
Egis Gyógyszergyár Nyrt.
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Publication date
Priority claimed from HU0400955A external-priority patent/HU0400955D0/hu
Priority claimed from HU0500463A external-priority patent/HUP0500463A3/hu
Priority to RSP-2006/0622A priority Critical patent/RS20060622A/sr
Priority to EP05745439A priority patent/EP1751138B9/fr
Priority to EA200602082A priority patent/EA010865B1/ru
Priority to US11/596,471 priority patent/US20070232662A1/en
Priority to JP2007512358A priority patent/JP2007537228A/ja
Priority to MXPA06013065A priority patent/MXPA06013065A/es
Priority to DE602005004024T priority patent/DE602005004024T2/de
Priority to AU2005240844A priority patent/AU2005240844A1/en
Application filed by Egis Gyógyszergyár Nyrt. filed Critical Egis Gyógyszergyár Nyrt.
Priority to CA002566426A priority patent/CA2566426A1/fr
Priority to SK5106-2006A priority patent/SK51062006A3/sk
Priority to PL05745439T priority patent/PL1751138T3/pl
Publication of WO2005108390A1 publication Critical patent/WO2005108390A1/fr
Priority to IL179030A priority patent/IL179030A0/en
Priority to HR20060403A priority patent/HRP20060403A2/xx
Priority to NO20065661A priority patent/NO20065661L/no
Priority to HR20080129T priority patent/HRP20080129T3/xx
Priority to US12/500,335 priority patent/US20090281137A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to new 3,3-disubstiruted indol-2-one derivatives, a process for the preparation thereof, pharmaceutical compositions containing said new indol-2-one derivatives and the use of said compounds for the treatment of diseases.
  • R 1 and R 2 independently represent hydrogen, halogen, alkyl having 1 to 7 carbon atom(s) or sulfamoyl;
  • R 3 represents hydrogen or straight or branched chain alkyl having 1 to 7 carbon atom(s);
  • R 4 stands for alkyl having 1 to 7 carbon atom(s);
  • R 5 is hydrogen and R 6 denotes phenyl optionally carrying 1 to 3 substituent(s) selected from halogen and alkyl having 1 to 7 carbon atom(s) carrying 1 to 3 halogen substituent(s), or
  • R 5 and R 6 form, together with the adjacent carbon atoms of the tetrahydropyridine ring, phenyl or a 5- or 6-membered heterocyclic ring containing a sulfur as heteroatom, which may optionally carry a halogen substituent;
  • n 1, 2, 3, 4, 5 or 6
  • U.S. patent No. 4,452,808 discloses 4-aminoalkyl-indol-2-one derivatives having a selective D 2 receptor activity. These compounds can be used for the treatment of hypertension.
  • One of the compounds provided by this patent namely 4-[2-(di-N- propylamino)ethyl]-2(3H)-indolone, is used in the clinical treatment.
  • European patent No. 281,309 provides indol-2-one derivatives carrying an arylpiperazinyl-alkyl substituent in position 5, which can be applied for the treatment of psychotic conditions.
  • One of the compounds described in this patent namely 5-[2-[4-(l,2- benzisothiazol-3-yl)-l-piperazinyl]-ethyl]-6-chloro-l,3-dihydro- 2H-indol-2-one, exerts its activity by interaction with D 2 , 5-HT IA and 5-HT 2 receptors and is used in the clinical treatment.
  • European patent No. 376,607 discloses indol-2-one derivatives substituted in position 3 by an alkylpiperazinyl-aryl group, which exert their activity on 5-HTI A receptors and are useful for the treatment of central nervous disorders.
  • indol-2-one derivatives containing a substituted alkylpiperazmyl, substituted alkyl-piperidinyl or alkyl-cyclohexyl group in position 3 are disclosed. These compounds exert anti-psychotic activity.
  • Adaptation disorders constitute an important risk factor in the development of diseases of mental or psychosomatic origin, such as anxiolytic syndrome, stress disorder, depression, schizophrenia, disorders of the sense organs, gastrointestinal diseases, cardiovascular diseases or renal disorders.
  • the pharmaceuticals acting on 5-HT tA receptors that have been so far applied in the therapy are accompanied, however, by several drawbacks and undesired side-effects. It is a drawback that the anxiolytic effect can be achieved only after a treatment lasting for at least 10 - 14 days. Besides, after the initial administration an anxiogenic effect occurs. As to the side-effects, the occurrence of sleepiness, somnolence, vertigo, hallucination, headache, cognitive disturbances or nausea has often been observed.
  • the object of the present invention is to develop pharmaceutical ingredients which are devoid of the above-specified drawbacks and undesired side-effects characteristic of the active agents binding to 5-HTJA receptors and which, at the same time, can be used for the treatment of disorders of the central nervous system.
  • the invention is based on the recognition that the 3,3-dialkyl- substituted indol-2-one derivatives of the general Formula (I) possess a significant anxiolytic effect, but surprisingly - in contrast to the prior art compounds of similar structure - do not bind to 5- HTIA receptors.
  • the compounds according to the invention are devoid of the side-effects characteristic of the compounds binding to the said receptor.
  • R 1 and R 2 independently represent hydrogen, halogen, alkyl having 1 to 7 carbon atom(s) or sulfamoyl;
  • R 3 represents hydrogen or straight or branched chain alkyl having 1 to 7 carbon atom(s);
  • R 4 stands for alkyl having 1 to 7 carbon atom(s);
  • R is hydrogen and R denotes phenyl optionally carrying 1 to 3 substituent(s) selected from halogen and alkyl having 1 to 7 carbon atom(s) carrying 1 to 3 halogen substituent(s), or
  • R 5 and R 6 form, together with the adjacent carbon atoms of the tetrahydropyridine ring, a phenyl group or a 5- or 6-membered heterocyclic ring containing a sulfur as heteroatom, which may optionally carry a halogen substituent; is 1, 2, 3, 4, 5 or 6,
  • ком ⁇ онент used throughout this specification is intended to mean straight or branched chain saturated hydrocarbon groups having 1 to 7, preferably 1 to 4 carbon atom(s), (e.g. methyl, ethyl, 1-propyl, 2-propyl, n-butyl, isobutyl or tert. butyl group etc.)
  • the term facedhalogen encompasses the fluorine, chlorine, bromine and iodine atoms and is preferably chlorine or bromine.
  • the leaving group can be an alkylsulfonyloxy or arylsulfonyloxy group, e.g. methylsulfonyloxy or p-toluenesulfonyloxy group; or a halogen atom, preferably bromine or chlorine.
  • pharmaceutically acceptable acid addition salts relates to non-toxic salts of the compounds of the general Formula (I) formed with pharmaceutically acceptable organic or inorganic acids.
  • Inorganic acids suitable for salt formation are e.g. hydrogen chloride, hydrogen bromide, phosphoric, sulfuric or nitric acid.
  • organic acids formic, acetic, propionic, maleic, fumaric, succinic, lactic, malic, tartaric, citric, ascorbic, malonic, oxalic, mandelic, glycolic, phtalic, benzenesulfonic, p-toluene-sulfonic, naphthalic or methanesulfonic acids can be used.
  • carbonates and hydro-carbonates are also considered as pharma-ceutically acceptable salts.
  • R 1 and R independently represent hydrogen, straight or branched chain alkyl having 1 to 7 carbon atom(s) or halogen
  • R 3 is hydrogen or a straight or branched chain alkyl having 1 to 7 carbon atom(s)
  • R 4 represents straight or branched chain alkyl having 1 to 4 carbon atom(s)
  • R 5 denotes hydrogen and R stands for phenyl optionally carrying a halogen or a trifluoromethyl substituent, or R 5 and R 6 form, together with the adjacent carbon atoms of the tetrahydropyridine ring, a 5- or 6- membered heterocyclic ring containing a sulfur atom as heteroatom and optionally carries a halogen atom, preferably chlorine, m is 3, 4 or 5, and pharmaceutically acceptable acid addition salts thereof.
  • R 1 , R 2 and R 3 independently represent hydrogen or halogen
  • R 4 is ethyl
  • R 5 and R 6 form, together with the adjacent carbon atoms of the dihydro-pyridine ring, a 5-membered heterocyclic ring containing sulfur as heteroatom, which optionally carries a halogen
  • m is 5, and pharmaceutically acceptable acid addition salts thereof.
  • R 1 , R 2 and R 3 independently represent hydrogen or halogen
  • R 4 is ethyl
  • R 5 stands for hydrogen
  • R 6 is phenyl carrying a halogen substituent, preferably fluorine
  • m is 4, and pharmaceutically acceptable acid addition salts thereof.
  • R , ⁇ -R are as stated above and L is a leaving group, preferably chlorine or bromine, m is 1, 2, 3, 4, 5 or 6 radical with a pyridine derivative of the general Formula (III),
  • L is sulfonyloxy or halogen, preferably chlorine or bromine; R 5 and R 6 are as stated above; m is 1, 2, 3, 4, 5 or 6, in the presence of a strong base, and optionally halogenating the thus-obtained product, wherein R 2 is hydrogen, or liberating the free base from a salt thereof or converting it into a pharmaceutically acceptable, organic or inorganic acid addition salts thereof.
  • the desired substituents can be introduced or converted according to methods known from the literature during any one of the reaction steps. If desired, following the application of any process variant the free base corresponding to the product of the general Formula (I) can be liberated from its salt or converted into a pharmaceutically acceptable acid addition salts thereof.
  • the compound of the general Formula (I) can be prepared by reacting a compound of the general Formula (LT) - wherein R ! -R 4 and m are as stated above and L is a leaving group, preferably bromine or chlorine, - with a compound of the general Formula (III) - wherein R 5 and R 6 are as stated above - according to methods known from the literature [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1992, 4 th Edition, vol. E16d (ed.: D. Klamann); R. C. Larock: Comprehensive Organic Transformations, 2 th Edition, John Wiley & Sons, New York, 1999, 789; D. A. Walsh, Y-H. Chen, J. B. Green, J. C. Nolan, J. M. Yanni J. Med. Chem. 1990, 35, 1823-1827].
  • the compounds of the general Formula (II) are preferably prepared by reacting a compound of the general Formula (V) — wherein L and m are as stated above and L' is a leaving group or a group that can be converted into a leaving group - with a compound of the general Formula (TV), wherein R ! -R 4 are as stated above [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4 th Edition, vol. V/2b; A. R. Katritzky, Ch. W.
  • the compounds of the general Formula (I) can also be prepared according to process variant (c) by reacting a compound of the general Formula (IV) - wherein R !
  • the compound of the general Formula (TV), wherein R -R 4 are as stated above, can be prepared by applying known methods, the formation of the substituents is carried out in optional succession according to methods known from the literature [A. R. Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1 th Edition, Pergamon, Oxford, 1984, vol. 4 (ed.: C. W. Bird, G. W. H. Cheeseman), 98-150 and 339-366; C. Gautier, M. Aletru, Ph. Bovy WO 99/62900; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595- 597; G. M. Karp Org. Prep. Proc. Int. 1993, 25, 481-513; A. S. Kende, J. C. Hodges Synth. Commun. 1982, 12, 1-10].
  • the compounds of the general Formula (I) prepared by the methods according to the invention can be liberated from their salts or converted into pharmaceutically acceptable acid addition salts according to methods known from the literature.
  • compositions comprising as active ingredient a compound of the general Formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with one or more conventional carrier(s) or auxiliary agent(s).
  • the pharmaceutical compositions according to the present invention contain generally 0,1-95 % by weight, preferably 1-50 % by weight, particularly 5-30 % by weight of the active ingredient.
  • the pharmaceutical compositions of the present invention may be suitable for oral (e.g. powders, tablets, coated tablets, capsules, microcapsules, pills, solutions, suspensions or emulsions), parenteral (e.g. injection solutions for intravenous, intramuscular, subcutaneous or intraperitoneal use), rectal (e.g. suppositories) transdermal (e.g. plasters) or local (e.g. ointments or plasters) administration or for the application in form of implants.
  • the solid, soft or liquid pharmaceutical compositions according to the invention may be produced by methods conventionally applied in the pharmaceutical industry.
  • the solid pharmaceutical compositions for oral administration containing the compounds of the general Formula (I) or pharmaceutically acceptable acid addition salts thereof may comprise fillers or carriers (such as lactose, glucose, starch, potassium phosphate, micro-crystalline cellulose), binding agents (such as gelatine, sorbite, polyvinyl pyrrolidone), disintegrants (such as croscarmelose, Na-carboxy-methyl cellulose, crospovidone), tabletting auxiliary agents (such as magnesium stearate, talc, polyethylene glycol, silicic acid, silicon dioxide) and surface-active agents (e.g. sodium lauryl sulfate).
  • fillers or carriers such as lactose, glucose, starch, potassium phosphate, micro-crystalline cellulose
  • binding agents such as gelatine, sorbite, polyvinyl pyrrolidone
  • disintegrants such as croscarmelose, Na-carboxy-methyl cellulose, crospovidone
  • tabletting auxiliary agents such as
  • compositions suitable for oral administration can be solutions, suspensions or emulsions.
  • Such compositions may contain suspending agents (e.g. gelatine, carboxymefhyl cellulose), emulsifiers (e.g. sorbitane mono-oleate, solvents (e.g. water, oils, glycerol, propyleneglycol, ethanol), buffering agents (e.g. acetate, phosphate, citrate buffers) and pre-servatives (e.g. methyl-4- hydroxybenzoate etc.).
  • suspending agents e.g. gelatine, carboxymefhyl cellulose
  • emulsifiers e.g. sorbitane mono-oleate
  • solvents e.g. water, oils, glycerol, propyleneglycol, ethanol
  • buffering agents e.g. acetate, phosphate, citrate buffers
  • pre-servatives e.g. methyl-4-
  • Liquid pharmaceutical compositions suitable for parenteral administration are generally sterile izotonic solutions optionally containing, in addition to the solvent, buffering agents and preservatives.
  • Soft pharmaceutical compositions containing as active ingredient a compound of the general Formula (I) or a pharmaceutically acceptable acid addition salt thereof, such as suppositories contain the active ingredient evenly dispersed in the basic material of the suppository (e.g. in polyethylene glycol or cocoa butter).
  • an indol-2-one derivative of the general Formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of pharmaceutical compositions suitable for the treatment or prophylaxis of disorders of the central nervous system or psychosomatic disorders including anxiety syndromes, particularly generalized anxiety disorders, panic disease, compulsive disorder, social phobia, agoraphobia, phobias in connection with specific situations, post-traumatic stress disorders, post-traumatic memory disturbances, cognitive disturbances, sexual dysfunction of central nervous system origin, depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
  • an indol-2-one derivative of the general Formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of pharmaceutical compositions suitable for the treatment or prophylaxis of disorders of the central nervous system or psychosomatic disorders including anxiety syndromes, particularly generalized anxiety disorders, panic disease, compulsive disorder, social phobia, agoraphobia, phobias in connection with specific situations, post-traumatic stress disorders, memory disturbances caused by trauma, cognitive disturbances, sexual dysfunction of central nervous system origin, depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
  • compositions according to the present invention can be prepared by known methods of the pharmaceutical industry.
  • the active ingredient is admixed with pharma-ceutically acceptable solid or liquid carriers and/or auxiliary agents and the mixture is brought to galenic form.
  • the carriers and auxiliary agents together with the methods which can be used in the pharmaceutical industry are disclosed in the literature
  • the pharmaceutical compositions according to the present invention contain generally a dosage unit.
  • the daily dosage for human adults can be generally 0,1-1000 mg/kg body weight of a compound of the general Formula (I) or a pharmaceutically acceptable acid addition salts thereof. Said daily dose can be administered in one or more portion(s). The actual daily dose depends on several factors and is determined by the physician.
  • the compounds of the general Formula (I) or pharmaceutically acceptable acid addition salts thereof for the treatment or prophylaxis of disorders of the central nervous system and psychosomatic disorders including anxiety syndrome, particularly generalized anxiety disorders, panic disease, compulsive disorder, social phobia, agoraphobia, phobias in connection with specific situations, stress disorders, post-traumatic memory disorders, cognitive disturbances, sexual dysfunction of central nervous system origin, depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
  • anxiety syndrome particularly generalized anxiety disorders, panic disease, compulsive disorder, social phobia, agoraphobia, phobias in connection with specific situations, stress disorders, post-traumatic memory disorders, cognitive disturbances, sexual dysfunction of central nervous system origin, depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
  • the invention is based on the surprising recognition that the compounds of the general Formula (I) exert anxiolytic activity but do not bind to 5-HT ⁇ A receptors. Thus, it can be expected that they are devoid of the above-listed adverse side-effects characteristic of the ingredients binding to 5-HT receptors.
  • Binding of the compounds of the general Formula (I) to 5-HTI A receptors was investigated according to the method of Peroutka (S.J. Peroutka: J. Neurochem. 47, p. 529 (1986) ).
  • IC 50 is the concentration whereby the difference between whole binding and non-specific binding in the presence of 10 ⁇ M serotonin creatinine sulfate is 50%.
  • the compounds with an IC 50 value smaller than 100 nmol were considered effective in this test. The results are given in Table 1.
  • test compounds do not bind to 5-HTi receptors.
  • a wooden cross elevated to 50 cm above the floor, 15 cm wide with 100 cm long arms was used for the experiments.
  • the sides and ends of two opposite arms of the cross were equipped with 40 cm high walls, however, the arms were open to the 15 cm x 15 cm central area (closed arms).
  • the two other opposite arms were not encircled by walls (open arms).
  • mice Male Sprague-Dawley rats weighing 200-220 g were used for the experiments. The animals were placed in the central area of the equipment 60 min after treatment and the following four parameters have been observed for the 5 min test time: time spent in the open arms (sec), time spent in the closed arms (sec), number of entries into the open arms, number of entries into the closed arms. The effect was expressed as percent increase in either the time spent in the open arms or number of entries into the open arms. MEDs (minimal effective doses) were determined for each compound. The results are summarized in Table 5.
  • the compounds according to the invention show a considerable efficacy in the treatment of disorders of the central nervous system. They may prove particularly suitable for the treatment of anxiety disorders, mixed anxiety and depression or in case of other disorders characterized by extreme stress conditions requiring tranquilliz-ation of the patient. They can also be used for the treatment of psychosomatic diseases, such as hypertension of psychic origin, gastrointestinal ulcer, colitis, asthma etc. In case of these clinical patterns it can be supposed that chronic stress, anxiety and/or unprocessed conflicts are in the background.
  • the new compounds according to the invention surprisingly do not exert their favourable therapeutic activity via 5-HTIA receptors, so it can be expected that they are devoid of the side-effects characteristic of the active ingredients acting on 5-HTI A receptors.
  • 3-ethyl oxindole (16.1 g; 0.10 mole) is dissolved in 350 ml of acetonitrile, the solution is cooled to 0 °C, and a solution of N- bromosuccinimide (17.8 g; 0.10 mole) in 150 ml of acetonitrile is dropped to it at the same temperature within 2 hours.
  • the reaction mixture is stirred first at 0 °C for 1 hour and then at room temperature for 3 hours.
  • the solution is evaporated, the white substance separated in crystalline form is extracted with dichloromethane and 1 M ⁇ aOH solution, and the organic phase is extracted again with alkaline water in order to remove succinimide.
  • the organic phase is dried over sodium sulfate, filtered and evaporated.
  • the separated white substance is recrystalhzed from a mixture of heptane and ethyl acetate. Yield: 15.24 g of white powder (63 %).
  • n-butyl lithium 60 ml; 0.15 mole
  • 200 ml of THF are added to it, and the solution is cooled in an acetone-dry ice bath to -78 °C.
  • a solution of the appropriate 3-alkyl oxindole (0.20 mole) in 250 ml of THF is dropped to it under stirring.
  • a dihaloalkane (l-bromo-4-chlorobutane, 1- bromo-3-chloropropane, 1,5-dibromopentane or 1,6- dibromohexane; 0,50 mole) is added dropwise to it, and the solution is allowed to warm up to room temperature. Then it is stirred further for 3 hours, and 20 ml of ethanol is dropped to it in order to decompose excess of butyl lithium.
  • the solution is distilled with a rotary evaporator and the residual oil is extracted with water and ethyl acetate. The organic phase is dried over sodium sulfate.
  • the residual oil is made crystalline by trituration with hexane.
  • the separated off-white crystals are stirred in 200 ml of hexane in order to remove excess of dihaloalkane, filtered and washed with hexane.
  • the product is used for the further reactions without recrystallization.
  • Analytical samples may be obtained by recristallization from the indicated solvent.
  • the title compound is prepared according to process "A” starting from 3-ethyl-5-fluoro-l,3-dihydro-2H-indol-2-one and l-bromo-4- chioro-butane.
  • the title compound is prepared according to process "A” starting from 3-ethyl-l,3-dihydro-2H-indol-2-one and l-bromo-3- chloropropane.
  • the title compound is prepared according to process "A” starting from 3-ethyl-5-fluoro-l,3-dihydro-2H-indol-2-one and 1,5- dibromopentane.
  • the title compound is prepared according to process "A” starting from 3-ethyl-5-methyl-l,3-dihydro-2H-indol-2-one and 1,5- dibromopentane.
  • the title compound is prepared according to process "A” starting from 3-ethyl-6-fluoro-l,3-dihydro-2H-indol-2-one and 1,5- dibromopentane.
  • the haloalkyl compound (5 mmoles) is dissolved in 15 ml of glacial acetic acid, the solution is cooled until glacial acetic acid begins to separate (14-16 °C) and a solution of 0.5 ml (5.7 mmoles) of sulfuryl chloride in 5 ml of glacial acetic acid is dropped to it. The mixture is stirred for 2 hours at the same temperature and then pipetted onto ice-water. The separated white substance is filtered, washed with water and hexane, dried and used for the coupling reaction without purification. Analytical samples may be obtained by recrystallization from the indicated solvent.
  • the title compound is prepared according to process "B” starting from 6-fluoro-3-(4-chlorobutyl)-3-ethyl- 1 ,3-dihydro-2H-indol-2- one.
  • the chloroalkyl compound is dissolved in 80 ml (40 mmoles) of glacial acetic acid, 9.6 ml (120 mmoles) of sulfuryl chloride are dropped to it at room temperature and the solution is kept at 60 °C for 3 hours. Then the reaction mixture is cooled, poured onto ice and extracted with diethyl ether. The ether phase is extracted twice with 10 % by volume NaOH solution, dried over sodium sulfate and evaporated. The thus-obtained pale yellow oil is triturated with hexane, the white substance separated in crystalline form is stirred in hexane, filtered, washed with hexane, dried again and used for the coupling reaction without purification. Analytical samples may be obtained from the given compounds by recrystallization from the indicated solvents.
  • 3-(4-Chlorobutyl)-3-ethyl-l,3-dihydro-2H-indol-2-one (12.59 g; 50 mmoles) is dissolved in the mixture of 100 ml of dioxane and 100 ml of water.
  • a mixture of 2.84 ml of bromine (55 mmoles), 11.9 g of KBr (100 mmoles) and 50 ml of water is dropped to the solution at a temperature between 80 °C and 90 °C within half an hour.
  • the reaction mixture is kept at the same temperature for further half an hour and allowed to cool.
  • 500 ml of water is dropped to it.
  • the product separates in form of white crystals.
  • the separated substance is filtered off, washed with water and hexane and used for the coupling reaction without purification.
  • Analytical samples may be obtained by recrystallization from a mixture of hexane and ethyl acetate. M.p.: 117-118 °C (hexane-ethyl acetate).
  • the product purified by column chromatography gets crystalline upon trituration with diethyl ether, it is filtered off and recrystalhzed from the solvent indicated after the melting point of the given substance.
  • the desired compounds are obtained in form of white crystals.
  • Process LittleD processing method 2 If the basic product does not get crystalline upon the addition of diethyl ether, it is dissolved in 200 ml of ether, the slight amount of floating precipitate is filtered off, and to the pure solution a solution of the calculated amount (one molar equivalent) of hydrogen chloride in 50 ml of diethyl ether is added under vigorous stirring. The separated white salt is filtered, washed with ether and hexane and dried in a vacuum pistol at room temperature for 3 hours. If necessary, the hydrochloride salt is recrystalhzed.
  • the title compound is prepared according to process "D” by applying processing method 1 starting from 3-(3-chloropropyl)-3- ethyl-l,3-dihydro-2H-indol-2-one and 2-chloro-6,7-dihydro-4H- thieno [3 ,2-c]pyridine.
  • the title compound is prepared according to process "D” by applying processing method 1 starting from 5-chloro-3-(3- chloropropyl)-3-ethyl-l,3-dihydro-2H-indol-2-one and 2-chloro- 6,7-dihydro-4H-thieno[3,2-c]-pyridine. M.p.: 66-69 °C (hexane-ethyl acetate).
  • the title compound is prepared according to process "D” by applying processing method 3 starting from 3-(4-chlorobutyl)-3- ethyl-l,3-dihydro-2H-indol-2-one and 4-(3-trifluoromethyl- phenyl)- 1,2, 3 ,6-tetrahydropyridine. M.p.: 136-139 °C.
  • the title compound is prepared according to process D by applying processing method 1 starting from 5-chloro-3-(4-chlorobutyl)-3- ethyl-l,3-dihydro-2/J-indol-2-one and 6,7-dihydro-4H-thieno[3,2- cjpyridine. M.p.: 213-215 °C.
  • the title compound is prepared according to process D by applying processing method 1 starting from 5-bromo-3-(4-chlorobutyl)-3- ethyl-l,3-dihydro-2H-indol-2-one and 6,7-dihydro-4H-thieno[3,2- cjpyridine.
  • the title compound is prepared according to process "D” by applying processing method 1 starting from 3-(4-chlorobutyl)-3- isobutyl-l,3-dihydro-2H-indol-2-one and 6,7-dihydro-4H- thieno[3 ,2-c]pyridine.
  • the title compound is prepared according to process "D” by applying processing method 1 starting from 3-(4-chlorobutyl)-3- ethyl-5-methyl-l,3-dihydro-2H-indol-2-one and 6,7-dihydro-4H- thieno[3,2-c]pyridine.
  • the title compound is prepared according to process "D” by applying processing method 1 starting from 3-(4-chlorobutyl)-3- etl yl-6-fluoro-l,3-dihydro-2H-indol-2-one and 6,7-dihydro-4H- thieno [3 ,2-c]pyridine. M.p.: 167-168 °C.
  • the title compound is prepared according to process "D” starting from 7-chloro-3-(4-chlorobutyl)-3-ethyl-5-fluoro-l ,3-dihydro-2H- indol-2-one and 6,7-dihydro-4H-thieno[3,2-c]-pyridine.
  • the product is isolated from the reaction mixture by applying processing method 1. M.p.: 194-196 °C (ethanol).
  • the title compound is prepared according to process "D” starting from 3-(4-chlorobutyl)-3-ethyl-l,3-dihydro-2H-indol-2-one and 2- chloro-6,7-dihydro-4JJ-thieno[3,2-c]pyridine.
  • the product is isolated from the reaction mixture by applying processing method
  • the title compound is prepared according to process "D” starting from 5-chloro-3-(4-chlorobutyl)-3-efhyl-6-fluoro-l,3-dihydro-2H- indol-2-one and 6,7-dihydro-4H-fhieno[3,2-c]-pyridine.
  • the product is isolated from the reaction mixture by applying processing method 1. M.p.: 155-157 °C (ethanol).
  • the title compound is prepared according to process ⁇ D" starting from 3-(5-bromopentyl)-3-ethyl-l,3-dihydro-2H-indol-2-one and 6,7-dihydro-4H-thieno[3,2-c]pyridine.
  • the product is isolated from the reaction mixture by applying processing method 3. M.p.: 193-195 °C.
  • the title compound is prepared according to process "D" starting from 3-(4-chlorobutyl)-3-ethyl-l,3-dihydro-2H-indol-2-one and 3,4-dihydro-lH-isoq noline.
  • the product is isolated from the reaction mixture by applying processing method 2. M.p.: 113-115 °C.
  • Example 40 3. ⁇ 4.[4-(4.Chlorophenyl)-3,6-dihydro-2H-pyridin-l-yl]-butyl ⁇ -3- ethyl- 1 ,3 -dihydro-2H-indol-2-one
  • the title compound is prepared according to process D starting from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-l,3-dihydro-2H-indol-2- one and 4-(3-chlorophenyl)-l,2,3,6-tetrahydro-pyridine.
  • the product is isolated by processing method 1.
  • the title compound is prepared according to process D starting from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-l,3-dihydro-2H-indol-2- one and 4-(4-chlorophenyl)-l,2,3,6-tetrahydro-pyridine.
  • the product is isolated using processing method 1.
  • the title compound is prepared according to process D using 3-(4- chlorobutyl)-3-ethyl-6-fluoro-l,3-dihydro-2H-indol-2-one and 4- (3-chlorophenyl)-l,2,3,6-tetrahydro-pyridine as starting compound.
  • the product is isolated according to processing method 2.

Abstract

L'invention porte sur de nouveaux dérivés du 3,3-disubstitué indol-2-one de formule générale (I) s'avérant utiles pour le traitement ou la prophylaxie de troubles du SNC, du système gastro-intestinal ou du système cardio-vasculaire.
PCT/HU2005/000051 2004-05-11 2005-05-11 Derives de l'indol-2-one traitant les troubles du snc, gastro-intestinaux, et cardio-vasculaires WO2005108390A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
SK5106-2006A SK51062006A3 (sk) 2004-05-11 2005-05-11 Indol-2-ónové deriváty na liečenie ochorení centrálneho nervového systému, gastrointestinálnych a kardiovaskulárnych ochorení
PL05745439T PL1751138T3 (pl) 2004-05-11 2005-05-11 Pochodne indol-2-onu do leczenia chorób centralnego układu nerwowego, chorób układu pokarmowego oraz chorób układu krążenia
CA002566426A CA2566426A1 (fr) 2004-05-11 2005-05-11 Derives de l'indol-2-one traitant les troubles du snc, gastro-intestinaux, et cardio-vasculaires
EA200602082A EA010865B1 (ru) 2004-05-11 2005-05-11 Производные индол-2-она для лечения расстройств центральной нервной системы, желудочно-кишечных расстройств и сердечно-сосудистых расстройств
US11/596,471 US20070232662A1 (en) 2004-05-11 2005-05-11 Indol-2-One Derivatives for the Treatment of Central Nervous Disorders, Gastrointestinal Disorders and Cardiovascular Disorders
JP2007512358A JP2007537228A (ja) 2004-05-11 2005-05-11 中枢神経系、胃腸系及び循環系の疾患の治療のためのインドール−２−オン誘導体
MXPA06013065A MXPA06013065A (es) 2004-05-11 2005-05-11 Derivados de indol-2-ona para el tratamiento de trastornos del sistema nervioso central, trastornos gastrointestinales y trastornos cardiovasculares.
DE602005004024T DE602005004024T2 (de) 2004-05-11 2005-05-11 Indol-2-onderivate zur behandlung von erkrankungen des zentralen nervensystems, erkrankungen des magen-darm-trakts und herzkreislauferkankungen
AU2005240844A AU2005240844A1 (en) 2004-05-11 2005-05-11 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders
RSP-2006/0622A RS20060622A (en) 2004-05-11 2005-05-11 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders
EP05745439A EP1751138B9 (fr) 2004-05-11 2005-05-11 Derives de l'indol-2-one traitant les troubles du snc ainsi que les troubles gastro-intestinaux et cardio-vasculaires
IL179030A IL179030A0 (en) 2004-05-11 2006-11-02 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders
HR20060403A HRP20060403A2 (en) 2004-05-11 2006-11-20 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders
NO20065661A NO20065661L (no) 2004-05-11 2006-12-06 Indol-2-onderivater for behandling av sentralnerveforstyrrelser, gastrointestinale forstyrrelser og kardiovaskulaere forstyrrelser
HR20080129T HRP20080129T3 (en) 2004-05-11 2008-03-20 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders
US12/500,335 US20090281137A1 (en) 2004-05-11 2009-07-09 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HUP0400955 2004-05-11
HU0400955A HU0400955D0 (en) 2004-05-11 2004-05-11 Pyridine derivatives of dialkyl oxindoles
HUP0500463 2005-05-05
HU0500463A HUP0500463A3 (en) 2005-05-05 2005-05-05 Pyridine derivatives of dialkyl-oxindoles

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US12/500,335 Division US20090281137A1 (en) 2004-05-11 2009-07-09 Indol-2-one derivatives for the treatment of central nervous disorders, gastrointestinal disorders and cardiovascular disorders

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AU (1) AU2005240844A1 (fr)
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CA (1) CA2566426A1 (fr)
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HR (2) HRP20060403A2 (fr)
IL (1) IL179030A0 (fr)
MX (1) MXPA06013065A (fr)
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PL (2) PL381614A1 (fr)
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JP2007537225A (ja) * 2004-05-11 2007-12-20 エギシュ ヂョヂセルヂャール エンニュ・エル・テー ５−ｈｔ７活性剤としてのアルキルオキシインドールのピリジン誘導体

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Publication number Priority date Publication date Assignee Title
WO2005109987A2 (fr) * 2004-05-11 2005-11-24 Egis Gyógyszergyár Nyrt. Nouveaux derives piperazine d'oxindoles de dialkyle
WO2005109987A3 (fr) * 2004-05-11 2006-05-04 Egyt Gyogyszervegyeszeti Gyar Nouveaux derives piperazine d'oxindoles de dialkyle
JP2007537225A (ja) * 2004-05-11 2007-12-20 エギシュ ヂョヂセルヂャール エンニュ・エル・テー ５−ｈｔ７活性剤としてのアルキルオキシインドールのピリジン誘導体
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EA014236B1 (ru) * 2004-05-11 2010-10-29 Эгиш Дьёдьсердьяр Нирт. Новые пиперазиновые производные диалкилоксиндолов

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CA2566426A1 (fr) 2005-11-17
RS20060622A (en) 2008-06-05
ES2299033T3 (es) 2008-05-16
PL381614A1 (pl) 2007-06-11
HRP20060403A2 (en) 2007-04-30
EP1751138B1 (fr) 2007-12-26
ATE382045T1 (de) 2008-01-15
PL1751138T3 (pl) 2008-05-30
EP1751138A1 (fr) 2007-02-14
EA200602082A1 (ru) 2007-04-27
MXPA06013065A (es) 2007-05-04
BG109770A (bg) 2008-05-30
JP2007537228A (ja) 2007-12-20
CZ2006772A3 (cs) 2007-03-14
DE602005004024D1 (de) 2008-02-07
DE602005004024T2 (de) 2008-12-24
SK51062006A3 (sk) 2007-04-05
IL179030A0 (en) 2007-03-08
NO20065661L (no) 2007-02-08
HRP20080129T3 (en) 2008-04-30
US20070232662A1 (en) 2007-10-04
KR20070014189A (ko) 2007-01-31
PT1751138E (pt) 2008-02-25

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